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Red wine ingredient may extend life

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SAN FRANCISCO, Aug 27, 2003 (United Press International via COMTEX) -- The fountain of youth may spring from a glass of red wine, at least for yeast, the toast of human aging research.

A compound found in the fruit of the vine extended life by up to 80 percent in Saccharomyces cerevisiae, a simple organism indispensable to bakers making bread and scientists seeking an aging antidote.

Researchers at Harvard Medical School in Boston and BIOMOL Research Laboratories, Inc., in Plymouth Meeting, Pa., used the potent red wine ingredient resveratrol and other plant-derived chemicals to duplicate in yeast and human cells the life-and-health-boosting benefits long attributed to low-calorie diets.

Over the past 70 years, research has shown mice, rats, worms, flies and yeast live longer when they curtail their calorie consumption. Such restricted food intake also appears to protect mammals against cancer and other diseases most prevalent among the elderly.

"It is too early to say whether we will be successful in our goal to slow or prevent diseases of old age," said lead study author David Sinclair, assistant professor of pathology at Harvard.

"Certainly the results are encouraging and exciting," he told United Press International. "From here on, the idea of having a pill that could dramatically improve health and extend life is no longer completely in the realm of science fiction."

Despite all the medical advances in the past 200 years, the maximum human lifespan has not budged from about 120, he noted. Tests on a number of lower organisms, however, have indicated their life line can be extended by restricting calories.

"If we are successful in developing drugs that mimic (calorie restriction), we would expect maximum as well as average lifespan to increase also," Sinclair said.

Even more important, the longer life would be devoid of disease. Mouse and monkey studies, for example, have shown calorie cutbacks of up to 75 percent can delay heart disorders and other ailments common to human seniors.

"It is a new ball game," Sinclair proclaimed. "The discovery points to a new line of research into drugs that could one day make people significantly healthier in their old age."

The achievement marks the first time scientists have found a molecule that not only mimics calorie restriction but also lacks side effects, the researchers said. In addition, the life extension was so significant Sinclair considers it a major breakthrough.

"We show how it might be possible to delay or prevent most of the diseases of the Western society with a simple pill," he said. "We can stimulate/activate the central regulators of lifespan, cell defense and survival, which means that all cells in the body might theoretically be made fitter and healthier with a pill."

In addition, the researchers present a new biological theory they say has major implications for life on Earth. Under the proposition, dubbed Xenohormesis, the scientists suggest the health benefits of calorie restriction are due to the organism's reaction against mild biological stress.

Although usually viewed as an adversary of good health, stress actually can drive an organism to slow its metabolism and conserve scarce resources, delaying death, the scientists explained.

They found certain plant-derived compounds called polyphenols -- found in fruit, nuts, vegetables, olive oil and other food groups -- work by activating certain key catalysts. These include the enzyme SIR2 in yeast, linked to extended life resulting from restricted food intake, and its human equivalent SIRT1.

"I think there is a good chance that SIRT1 is a master longevity regulator and that we've just taken a big step toward being able to manipulate its activity pharmacologically," Konrad Howitz, director of molecular biology at BIOMOL, told UPI.

Resveratrol, the most powerful of the chemicals tested and previously shown to protect against cancer, atherosclerosis and other age-related diseases, is present in the food products of many plants, but it abounds in red wine.

"Resveratrol is found in grape skins, from which it is extracted during the fermentation process," Howitz explained. "Stress on the plant, such as drought or lack of nitrogen, can raise the content of resveratrol, and this applies to other plants and their polyphenols as well."

Apparently, California grape vines experience less stress than those in Chile or Australia because the wine they produce contains smaller amounts of the health-promoting compound, Sinclair said.

Other, lesser sources of resveratrol include peanuts, grape juice, mulberries and the Japanese knotweed root, used in traditional Asian medicine.

"At the moment, the yeast system provides the most complete picture of how these compounds act," Howitz said. They appear to extend lifespan by minimizing mutations and maximizing the stability of an organism's genetic material, he explained.

"If this ability ... holds true for mammals, including humans, (it) would suggest that they would delay aging and along with it the onset of various age-related disorders, including cancer, heart disease, osteoporosis and diabetes," said Howitz, co-author of the paper published in the British journal Nature.

"The great hope that comes out of this work is that it may have moved us closer to finding interventions that simultaneously provide longer and healthier life."

The research builds on the pioneering work by Leonard Guarente, Novartis Professor of Biology at the Massachusetts Institute of Technology, in Cambridge, who described his pursuit of youth-prolonging genes in his book, "Ageless Quest" (Cold Spring Harbor Laboratory Press, 2002).

"(The new study) follows my lab's work showing that SIR2 regulated lifespan in accord with calorie restriction," Guarente said in a telephone interview. "It means we can hope for effective drugs in a 10-year time frame."

Guarente's search for a genetic "cure" for growing old has centered around the discovery of the SIR2 gene in yeast, which, he has argued, slows down aging in times of food scarcity. Because SIR2 has been found to extend youth in yeast and animals, some scientists have speculated it eventually could be used to do the same in humans.

"In the past few years, a new paradigm in aging research has emerged -- that aging can be regulated," Sinclair, who worked in Guarente's lab as a graduate student, said. "What this means is that we don't even need to know what the causes of aging are to be able to slow the process."

The polyphenols work by activating sirtuins, a family of enzymes known to extend the lifespan of tiny lab roundworms as well as yeast. In screening tests, the researchers found 17 molecules that stimulated SIRT1, one of seven human sirtuins, and the yeast sirtuin SIR2.

"Right now, our working hypothesis about this pathway is that it can buy a stressed or damaged cell a little extra time, to wait out the stress until conditions improve and/or repair damage that might have needlessly induced apoptosis, the cell suicide pathway," Howitz explained.

The researchers were surprised to find yeast cells treated with small doses of resveratrol lived for an average of 38 generations, twice the norm.

Because several parts of the study involved human cells, Howitz said, "at the very least, we know that these compounds activate SIRT1, the closest human relative of SIR2."

The average human lifespan has leaped from about 20 years for early humans to 80 or so for modern-day residents of industrialized countries, with most of the increase occurring in the past 150 years.

With a bit of pharmaceutical assistance, "we will be able to harness the benefit of calorie restriction -- about a 10-to-20-year extension," Guarente forecast.

The team now is looking for new sirtuin-activating compounds in yeast, roundworm and fruitfly longevity studies. If upcoming mouse investigations succeed, human testing will follow.

"Our goal is not to make people immortal and really not even to make them live longer but rather to help them be productive, healthy and happy longer," Guarente told UPI, "and that's in the cards with this research trajectory that we're on."

Copyright 2003 by United Press International.

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